Method and adsorbant composition for 82 Rb generation

ABSTRACT

A composition comprising 82Sr and an adsorbant selected from the group consisting of tin oxide, hydrated tin oxide, polyantimonic acid, titanium oxide, and ferric oxide. A low 82Sr breakthrough method of generating 82Rb from a 82Sr charged adsorbant comprising eluting wherein said adsorbant is selected from the group consisting of tin oxide, polyantimonic acid, titanium oxide, ferric oxide, and hydrated tin oxide.

This application is a continuation-in-part of application Ser. No. 162,858 filed June 25, 1980 abandoned.

BACKGROUND OF THE INVENTION

Rubidium-82, a positron emitter with a half-life of 75-sec readily obtainable from the parent Sr-82 (T_(1/2) =25 days). Rubidium can be used as a diffusible flow tracer for the myocardium and kidney, and as a nondiffusible tracer for brain blood flow. Serial injections of Rb-82 can be administered every 5 to 10 minutes by eluting (milking) Rb-82 from its 25-day Sr-82 parent. The advantages of Rb-82 are low radiation dose, ability to provide for repeated examinations every 5 minutes without constraints from body background, and a convenient and economical supply of a short-half-life positron emitter. (Yano et al., The Journal of Nuclear Medicine 20:961-966, 1979.)

Significant quantities of ⁸² Sr are available for clinical investigation. The short-lived daughter, 75-second ⁸² Rb, is a value in biomedicine for circulation and perfusion studies as well as for myocardial imaging as mentioned in U.S. Pat. No. 3,953,567.

Loc[h et al. J. Nucl. Med. 21: 171-173, 1980 disclose a tin dioxide (SnO₂)/HCl Ga-68 generator.

Arino et al. Int. J. Appl. Radiat. Isot. 29: 117-120, 1978 disclose a ⁶⁸ Ge/⁶⁸ Ga radioisotope generator system which uses polyantimonic acid to selectively adsorb Ge and not Ga. The adsorption was speculated to be due to a dehydration reaction forming chemical bonding between Sb and Ge through oxygen.

Neirinckx et al. disclose titanium oxide in a generator for ionic gallium-68, see second International Symposium on Radiopharmaceutical Chemistry MRC. Oxford, 1978, p. 109.

Kopecky et al. Int. J. Appl. Radiat. Isot. 25: 263-268, 1974 disclose a ⁶⁸ Ge/⁶⁸ Ga generator for the production of ⁶⁸ Ga in an ionic form. Aspects of the adsorption of carrier-free ⁶⁸ Ge and ⁶⁸ Ga on alumia, Al(OH)₃ and Fe(OH)₃ are discussed.

SUMMARY OF THE INVENTION

A composition comprising ⁸² Sr and an adsorbant selected from the group consisting of tin oxide, hydrated tin oxide, polyantimonic acid, and titanium oxide.

A low ⁸² Sr breakthrough method of generating ⁸² Rb from a ⁸² Sr charged adsorbant comprising eluting the ⁸² Rb from said adsorbant with an eluant solution wherein said adsorbant is selected from the group consisting of hydrated, unhydrated and mixtures of the hydrated and unhydrated forms of tin oxide, titanium oxide and ferric oxide; and unhydrated polyantimonic acid. The eluant can be physiological saline or a buffered isotonic solution. The yields of ⁸² Rb are high.

DETAILED DESCRIPTION OF THE INVENTION

Hydrated tin oxide includes hydrated stannic oxide, hydrated stannous oxide, and mixtures of hydrated stannic oxide and hydrated stannous oxide. Preferably the hydrated tin oxide is amorphous.

Tin oxide includes stannic oxide, stannous oxide and mixtures of stannous oxide and stannic oxide.

Most preferably an amorphous mixture comprising tin oxide and a substantial amount (more than 10% by weight) of hydrated stannic oxide is used as the adsorbant.

The method and compositions of the present invention are useful in positron imaging and in the subsequent measurement of blood flow through the myocardium, brain and kidneys.

The present invention provides improved breakthrough characteristics. It has been discovered that breakthrough of Sr may be lowered by providing an adsorbant which is preferably polyantimonic acid, titanium oxide (hydrated), ferric oxide (hydrated), hydrated tin oxide or tin oxide.

The present invention provides a small bolus size of 2-3 ml which is advantageous for lower volume per unit time infusion while maintaining an effective amount of activity to monitor the patient.

Preferably the eluant is isotonic saline or isotonic saline buffered at physiological pH. Preferably a buffered eluant is used and the buffer is a phosphate salt or a carbonate salt. Preferably the buffer is a phosphate salt. Most preferably isotonic saline at physiological pH is used.

Bacteriostats may be beneficially added to the eluant. Preferred bacteriostats are those which are pharmaceutically acceptable buffers, for example parabens.

Infusion speeds of 5-10 ml per minute or higher are useful when using the compositions and method of the present invention.

⁸² Rb yields of 90% of theoretical maximum are obtained using the present invention. These yields may be obtained over a 0.1 minute interval using an eluant flow rate of 30 ml/min.

Low ⁸² Sr breakthroughs of 10⁻⁹ /ml are obtained using the present invention.

Beneficially, the present invention provides high yields of ⁸² Rb with physiological saline as eluant and high radioactive concentration in the eluate (90% elution yield in 5-10 cc).

The eluant may be buffered at a pharmaceutically acceptable pH. Preferably the pH is from 6.0 to Ph 10. Most preferably the pH is from pH 7.0 to pH 7.5 The concentration of the buffer in the eluent preferably is from 0.01 mmol to 200 mmol per liter of eluant solution.

The saline concentration of the eluant is a pharmaceutically acceptable concentration. Preferably the saline is isotonic (0.9%).

A column containing adsorbant is charged with ⁸² Sr. Preferably the adsorbant is hydrated tin oxide or polyantimonic acid. Most preferably the adsorbant is hydrated tin oxide. The column is then eluted with the eluant.

At clinically useful flow rates of about 20 ml per minute, ⁸² Sr breakthroughs of 10⁻⁹ per ml of eluant are obtained by the present invention. Breakthrough is the ratio of microcuries of ⁸² Sr in the eluant to the microcuries of ⁸² Sr on the adsorber.

Phosphate salts include alkali phosphates, alkaline earth phosphates, alkali metal hydrogen phosphates, alkaline earth hydrogen phosphates as well as hydrates of phosphate salts. Also phosphate salts include all phosphorous oxides which form phosphates upon addition to water.

A preferred phosphate salt is Na₂ HPO₄ which may be added to the eluant as Na₂ HPO₄.7H₂ O. In the saline eluant it forms Na⁺ and PO₄ ⁻³ ⃡HPO₄ ⁻² ⃡H₂ PO₄.sup.⊖. Upon addition of NaOH some of the H₂ PO₄.sup.⊖ would be used up in the formation of HPO₄ ⁻². The balanced equation being:

    NaH.sub.2 PO.sub.4 +NaOH⃡Na.sub.2 HPO.sub.4 +H.sub.2 O.

When acid is added, for example HCl, some H₂ PO₄.sup.⊖ is formed. The balanced equation is:

    Na.sub.2 HPO.sub.4 +HCl⃡NaH.sub.2 PO.sub.4 +NaCl.

Carbonate salts include water soluble carbonate salts such as alkali metal carbonates and alkali metal hydrogen carbonates for example NaHCO₃. In water NaHCO₃ forms Na⁺ and CO₃ ⁻² ⃡H CO₃.sup.⊖ ⃡H₂ CO₃. Upon addition of NaOH; HCO₃ ⁻¹ and H₂ CO₃ are used up and CO₃ ⁻² and HCO₃ ⁻¹ respectively are formed. Upon addition of HCl; CO₃ ⁻² and HCO₃ ⁻ are used up and HCO₃ ⁻ and H₂ CO₃ respectively are formed.

The procedure used in examples 1-4 is as follows:

50 mg amounts of one of Ti(OH)₄, polyantimonic acid. SnO₂ (hydrated) or ferric oxide are shaken with 5 ml of liquid phase. The liquid phase is either isotonic saline (0.9% NaCl) or saline and phosphate salt solution. The phosphate concentrations are 0.25% and 0.025%. 0.02 ml of Sr-85 or Rb-83 is added. After one hour of equilibration 1 ml fractions are pipetted. The activity in each fraction is measured and the K_(D) calculated.

The SnO₂ (hydrated) used in Example 3 is sold by Applied Research Rue Hercoliers Brussels, Belgium as oxide d'etain hydrate, (which is French for hydrated tin oxide); OXTAIN (Trademark). This material is a chromatographic amorphous mixture comprising tin oxide and a substantial amount of hydrated stannic oxide. Upon heating, this material looses most of its Sr-Rb separation ability. Thus, there is a loss of activity with the loss of hydration of tin oxide.

    ______________________________________                                         Ex-                                                                            am-  Ad-                        K.sub.D                                                                               K.sub.D                                 ple  sorbents             pH    Sr-82  Rb-82                                   ______________________________________                                         1    Ti(OH).sub.4                                                                            saline (0.9%)   8   40,000  52                                                 saline + 0.025% PO.sub.4.sup.-3                                                                7.8 57,000  54                                                 saline + 0.25% PO.sub.4.sup.-3                                                                 8   71,000  56                                   2    poly-    saline (0.9%)   2.7 47,500 <3                                         antimonic                                                                               saline 0.025% PO.sub.4.sup.-3                                                                  2.7 114,000                                                                               <3                                         acid     saline + 0x.25% PO.sub.4.sup.-3                                                                4.6 64,000 <3                                    3    SnO.sub.2                                                                               saline (0.9%)   7.6 60,000 <3                                         (hy-     saline + 0.025% PO.sub.4.sup.-3                                                                7.6 41,000 <3                                         drated)  saline + 0.25% PO.sub.4.sup.-3                                                                 7.6 42,000 <3                                    4    Fe.sub.2 O.sub.3                                                                        saline (0.9%)   3.6   <3   <3                                         (hy-     saline + 0.025% PO.sub.4.sup.-3                                                                4.1    7   <3                                         drated)  saline + 0.25% PO.sub.4.sup.-3                                                                 6.5  1.182 <3                                    ______________________________________                                    

In Examples 1-4 the difference in K_(D) values for ⁸² Sr and ⁸² Rb shows the amount of separation. The high K_(D) values for ⁸² Sr and the low K_(D) values for ⁸² Rb show that ⁸² Sr is strongly adsorbed while ⁸² Rb is only slightly adsorbed. Thus, while a Sr loaded column of the adsorbants in Examples 1-4 is eluted with Sr remains adsorbed strongly with very minute breakthrough into the eluate. The daughter ⁸² Rb is only slightly adsorbed and passes out with the eluate in yields of about 90%.

The bolus volume is the amount of eluant needed to elute the available ⁸² Rb.

EXAMPLE 5

Into a column 2 inches long and one fourth inch in diameter is placed 1.5 cc of SnO₂ particles having diameters of from 0.05 to 0.1 mm. Pre-equilibrium is done by washing the SnO₂ (hydrated) with saline three times. 2 ml of Sr-82 in saline solution having a pH of about 11 is loaded onto the SnO₂ (hydrated) particles by gravity in about one minute. The column is eluted at 12 ml per minute. The multi scaler mode on a multi channel analyzer was used to determine the elution profile. The bolus volume is about 3.4 ml.

The column is allowed to equilibrate and then counted for 777 KeV(Rb-82) with a Ge(Li) detector.

Table 1 shows the eluant composition volumes and the breakthrough fraction of ⁸² Sr for each volume eluted.

Table 2 shows a Summary of Characteristics of ⁸² Rb Generator System using inorganic adsorbers. At the bottom of the table are shown the characteristics of the SnO₂ (hydrated) adsorbent of the present invention.

                  TABLE 1                                                          ______________________________________                                         BREAKTHROUGH OF .sup.82 Sr IN A                                                .sup.82 Rb GENERATOR HAVING A SnO.sub.2                                        (HYDRATED) ADSORBENT                                                                                            Fraction of Sr                                Eluant    Volume (CC)                                                                               pH Eluate   loaded/cc                                     ______________________________________                                         NaCl pH9   0-150     ˜1    --                                            "         150-160    1.5         7 × 10.sup.-6                           "         160-170    2           5 × 10.sup.-6                           "         170-200    2           7 × 10.sup.-6                           Na.sub.2 HPO.sub.4                                                             0.25%     200-205    6.5         2 × 10.sup.-6                           "         210-250    7           1.5 × 10.sup.-7                         Na.sub.2 HPO.sub.4                                                             0.025%    250-295    7           9 × 10.sup.-8                           pH9       295-348    7           7 × 10.sup.-8                           "         345-600    7           5 × 10.sup.-8                           "         600-650    7           10.sup.-8                                     "         650-700    7           2 × 10.sup.-8                           "         700-750    7           2 × 10.sup.-8                           "         750-800    7           5 × 10.sup.-9                           "         800-850    7           ≦5 × 10.sup.- 9                  "         850-900    7           ≦10.sup.-8                             "         900-950    7           ≦1.5 × 10.sup.-8                 "          950-1000  7           ≦10.sup.-8                             "         1000-1050  7           ≦2.5 × 10.sup.-8                 "         1050-1100  7           ≦10.sup.-8                             "         1100-1150  7           ≦2 × 10.sup.-8                   "         1150-1200  7           ≦2.5 × 10.sup.-8                 "         1200-1250  7           ≦5 × 10.sup.-9                   "         1250-1300  7           ≦2.5 × 10.sup.-8                 "         1300-1350  7           ≦3 × 10.sup.-8                   "         1350-1400  7           ≦5 × 10.sup.-9                   "         1400-1450  7           ≦1.5 × 10.sup.-8                 "         1450-1800  7           ≦5 × 10.sup.-9                   "         1500-1550  7           ≦10.sup.-8                             "         1550-1600  7           ≦1.5 × 10.sup.-8                 "         1600-2100  7.4         ≦10.sup.-8                             "         2100-3100  7.4         ≦5 × 10.sup.-10                  "         3100-3925                                                            "         3925-4600  7.4         1 × 10.sup.-9                           "         4600-5000  7.4         1 × 10.sup.-9                           ______________________________________                                          In Table I above a "≦" represents less than or equal to           

                                      TABLE 2                                      __________________________________________________________________________     SUMMARY OF CHARACTERISTICS OF .sup.82 Rb GENERATOR SYSTEMS                     USING INORGANIC ADSORBERS                                                              Column       Elution  Rb-82                                                                               Sr-82 Break-                                                                              No.                                      Size         Speed                                                                               Eluate                                                                             Yield                                                                               through    Elutions                         Adsorbent                                                                              (ml) Eluant Used                                                                            (ml/sec)                                                                            pH  %    (ml)       Tested                           __________________________________________________________________________     Al.sub.2 O.sub.3                                                                       1    NaCl 2% 1.2  8-9 70/10 ml                                                                            4 × 10.sup.-6                                                                       250                                           NaCl 0.9%                                                                              1.2  8-9 25/10 ml                                                                            5 × 10.sup.-6                                                                       250                              Al.sub.2 O.sub.3                                                                       2.25 NaCl 2% 0.5  8-9 76/20 ml                                                                            5 × 10.sup.-6 - 5 ×                                                10.sup.-8  300                              Al.sub.2 O.sub.3                                                                       2.75 NaCl 0.9%                                                                              5    7.5 35/20 ml                                                                            --         600                                      2.75 NaCl 0.9%                                                                              0.1  7.5 --   1 × 10.sup.-7                                                                       600                              ZrO.sub.2                                                                              2.75 NaCl 0.9%                                                                              5    7.5 56/20 ml                                                                            --         600                                      2.75 NaCl 0.9%                                                                              0.1  7.5 --   2 × 10.sup.-7                                                                       600                              SnO.sub.2 (hydrated)                                                                   1.5  PO.sub.4.sup.-3 buffered                                                               0.2  7.4 95/4 ml                                                                             ≦ 5 × 10.sup. -9                                                             1,000                            (of the      isotonic                                                          present      saline (pH9)                                                      invention)                                                                     __________________________________________________________________________ 

I claim:
 1. A composition comprising ⁸² Sr and an adsorbant selected from the group consisting of tin oxide, hydrated tin oxide, polyantimonic acid, titanium oxide, ferric oxide, hydrated ferric oxide and hydrated titanium oxide.
 2. The composition of claim 1 wherein said adsorbant is selected from the group consisting of hydrated tin oxide and polyantimonic acid.
 3. The composition of claim 1 wherein said adsorbant comprises chromatotographic particles, said particles comprising hydrated tin oxide.
 4. The composition of claim 3 wherein said ⁸² Sr is adsorbed on said adsorbant chromatographic particles, said particles having an average diameter of 0.01 to 0.9 mm.
 5. Apparatus for generating ⁸² Rb comprising container means and the composition of claim 4 contained within said container means, said particles having an average diameter of 0.05 to 0.1 mm.
 6. A low ⁸² Sr breakthrough method of generating ⁸² Rb from a ⁸² Sr charged adsorbant comprising eluting the ⁸² Rb from said adsorbant with an eluant solution wherein said adsorbant is selected from the group consisting of tin oxide, hydrated tin oxide, polyantimonic acid, hydrated titanium oxide, and hydrated ferric oxide.
 7. The method of claim 6 wherein said adsorbant is selected from the group consisting of tin oxide, hydrated tin oxide, and polyantimonic acid.
 8. The method of claim 7 further comprising providing container means and containing said ⁸² Sr charged adsorbant in said container means, said adsorbant comprising chromatographic particles having an average diameter of 0.01 to 0.9 mm.
 9. The method of claim 8 wherein said eluant solution comprises isotonic saline.
 10. The method of claim 9 wherein said eluant solution further comprises a pharmaceutically acceptable buffer.
 11. The method of claim 10 wherein said buffer comprises a phosphate salt or a carbonate salt.
 12. The composition of claim 3 wherein said hydrated tin oxide is a substantial amount of hydrated stannic oxide.
 13. The composition of claim 12 further comprising tin oxide, said composition being amorphous. 